AG-1284

A class of potent nonpeptidic inhibitors of human immunodeficiency virus protease has been designed by using the three-dimensional structure of the enzyme as a guide. By employing iterative protein cocrystal structure analysis, design, and synthesis the binding affinity of the lead compound was incrementally improved by over four orders of magnitude. An inversion in inhibitor binding mode was observed crystallographically, providing information critical for subsequent design and highlighting the utility of structural feedback in inhibitor optimization. These inhibitors are selective for the viral protease enzyme, possess good antiviral activity, and are orally available in three species.

Several preformulation characteristics of a series of novel HIV protease inhibitors were examined as a prelude to expedient oral dosage form development.Initial studies indicated that these compounds were orally bioavailable in rats (≤39%), but chem. unstable at low pH.AG1284 was selected as the lead compound from the series for further preclin. development based on its relatively high oral bioavailability and stability.The pH-rate profiles of AG1284 indicated a first-order degradative loss of a dimethylbenzyl group under acidic conditions.Concentrated solutions of an amorphous form prepared in various pharmaceutical solvents exhibited precipitation on standing.The precipitate was identified as crystalline AG1284 by X-ray powder diffraction, DSC, and polarized light/hot stage microscopy, and its solubility in water proved to be much lower than that of the amorphous form.Oral administration in dogs of a solid blend of AG1284 with polyethylene glycol 3350 (PEG 3350) in enteric-coated hard gelatin capsules did not yield any detectable AG1284 levels in plasma.When dosed in a propylene glycol/water (60/40) solution at 50 mg/kg to rats, oral bioavailability and C_max were 39% and 2.8 μg/mL, resp.When delivered in a lyophilizable emulsion to rats at 100 mg/kg, oral bioavailability and C_max were 31% and 3.0 μg/mL, resp.The lyophilized product could be reconstituted with WFI to regenerate an emulsion.